Delivery of drugs to mucosal surfaces

ABSTRACT

Liquid pharmaceutical compositions for administration to a mucosal surface, including fentanyl and a pectin with a low degree of esterification are described. Such compositions gel, or can be adapted to gel, at the site of application in the absence of an extraneous source of divalent metal ions.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.10/196,590, filed Jul. 15, 2002, which was a continuation of U.S. patentapplication Ser. No. 09/402,976, filed Jan. 20, 2000, now U.S. Pat. No.6,432,440, issued Aug. 13, 2002, which was a §371 filing ofInternational Application No. PCT/GB98/01147, filed Apr. 20, 1998,published in the English language on Oct. 29, 1998, under InternationalPublication No. WO 98/47535, the contents of each of which areincorporated herein by reference.

BACKGROUND OF THE INVENTION

This invention relates to an improved system for the delivery of drugsto mucosal surfaces such as the nose, the eye, the vagina, the rectumand the back of the throat.

Administration of therapeutic agents to mucosa is well known in the art.

A variety of drugs may be administered to the nose, including thoseintended for the local treatment of nasal diseases, nasal vaccines, andthose intended for systemic circulation. Because the nose has areasonable surface area and a good blood supply, certain lipophilicdrugs, such as nicotine and propranolol, can be absorbed rapidly intothe blood, resulting in a bioavailability which is similar to that seenwith intravenous injection. More polar drugs are less well absorbed,though absorption may be improved by the use of enhancing agents such assurfactants, powders such as microcrystalline cellulose, gellingmicrospheres (e.g., starch), and the bioadhesive polymer, chitosan.Examples of these systems are well known in the art and have beenreviewed by Illum and Fisher in “Inhalation Delivery of TherapeuticPeptides and Proteins”, Adjei and Gupta (eds.) Marcel Dekker Inc., NewYork (1997) 135-184.

In a similar fashion, it is useful to deliver therapeutic agents, suchas drugs and vaccines, to the vaginal cavity for a systemic effect orfor the local treatment of diseases (particularly infectious diseasessuch as candidiasis and bacterial vaginitis) as well as for prophylaxisof diseases (e.g., HIV). Locally acting formulations may also be used todeliver contraceptive and spermicidal agents.

Drugs may also be administered to mucosa in the eye and the rectum inorder to achieve local effects or for systemic activity.

Considerable advantages in terms of improved efficacy are expected to begained if a nasally administered formulation were capable of retaining adrug, a vaccine, or DNA intended for local effect, in the nose forrelatively long time periods. Previous workers have used a variety ofstrategies for this purpose.

For example, Illum and others found that biodegradable microspheresbased on materials such as starch could delay clearance to a period ofhours as compared to a normal half life of clearance of about 10 to 15minutes (Illum, et al., Int. J. Pharm., 39 (1986) 189-199).Surprisingly, such systems were also found to give an improvedabsorption by affecting the integrity of the tight junctions of theepithelial cells in the nasal cavity and are expected therefore to bebest suited to drugs acting systemically.

Similarly, Illum and others have shown that the bioadhesive materialchitosan can modify mucociliary clearance with an increase in drugabsorption (Illum, et al., Pharm Res., 11 (1994) 1186-1189).

It would be most beneficial, due to ease of use and of administration,to have available a simple solution spray system that was suitable forthe administration of drugs to the nose and, better still, for the drugsadministered via such a system to have a long retention in the nasalcavity. The skilled person may envisage various strategies to this end,including the use of pharmacological agents that decrease mucociliaryclearance by a direct effect on the action of cilia, such as cocaine, aswell as formulation methods such as environmentally-responsive gels.

Liquids that gel in response to a change in environment are known tothose skilled in the art. The environmental change can be temperature,pH or ionic strength or a combination of these factors. Examples of allof these systems can be found in the prior art literature (see, forexample, the smart hydrogel from Gelmed as described by Potts et al inProceed. Intern. Symp. Control Rel., 24, 335 (1997)). However, themajority of these have been found to be unsuitable for nasal use in manbecause of factors such as irritation, discomfort (e.g., administrationof cold solutions), mucosal damage, an unwanted enhancement of drugabsorption into the systemic circulation, and many are unavailable dueto lack of regulatory approval.

In summary, it would present considerable advantages to provide a singlecomponent nasal delivery system, which was in the form of a liquid forease of administration, and in particular one that gelled in the noseupon contact with the nasal tissues, which could be used to administer,and to modify absorption characteristics, of drugs (therapeutic agents)intended to act locally or systemically. It would also be desirable toprovide a system which is well accepted by patients, does not enhancethe absorption of drug intended for a local effect into the systemiccirculation (as this could lead to side effects), and comprisesmaterials that are approved by regulatory authorities.

Those skilled in the art will appreciate that there are similar problemsto be solved in respect of drug delivery for the improved treatment ofconditions that affect the vaginal cavity, the rectum, the eye, and theback of the throat, as well as for the improved delivery of vaccines tothe local lymphoid tissue, or for the improved delivery of DNA for thetransfection of epithelial cells.

For example, drugs intended for the treatment of vaginal infections, ordrug free formulations intended to act as vaginal moisturizing agents(especially useful in post-menopausal conditions), should spread well inthe vaginal cavity and be retained for long periods of time. However, ithas been reported that so-called bioadhesive formulations that areintended to be retained in the vaginal cavity for days can be expelledrapidly, with more that 80% of the dose leaving the vagina in less than2 hours (Brown, et al., 14, 1073 (1997)). Thus, it would be advantageousto provide a single component liquid composition that could be insertedinto the vagina as a simple liquid and that gelled under the localenvironmental conditions to give good retention.

For rectal enemas, it would be most beneficial if the liquid enemaformed a gel once applied, ensuring close contact with the localenvironment and preventing early discharge.

Similar problems may be identified in respect of administration to theeye, by virtue of the fact that liquid formulations are rapidly clearedfrom the eye through drainage down the naso-lacrymal duct. A singlecomponent liquid composition that gelled upon application to the eyewould be advantageous for the treatment of conditions such as eyeinfections and inflammation.

Pectins are materials which are found in the primary cell wall of allgreen land plants. They are heterogeneous materials, with apolysaccharide backbone that is uniform as α-1,4-linked polygalacturonicacid. Various neutral sugars have been identified in pectins such asxylose, galactose, rhamnose, and arabinose.

A critical property of pectins which is known to affect their gelationproperties, is the extent to which the galacturonic acid units areesterified. The degree of esterification (DE) of pectins found naturallycan vary considerably (from 60 to 90%). The term DE is well understoodby those skilled in the art and may be represented as the percentage ofthe total number of carboxyl groups which are esterified, or as themethoxyl content of the pectin. The respective theoretical maximum foreach is 100% and 16% respectively. DE as used herein refers to the totalnumber of carboxyl groups which are esterified. Low DE pectins (i.e.,those having less than 50% esterification) are usually prepared by thede-esterification of extracted pectins, normally on a bench scale, byway of an enzymatic process, or, on an industrial scale, by thetreatment with acid or ammonia in an alcoholic heterogeneous medium. Forpectins with a low degree of methoxylation (DM; less than 45%) thegelation properties are known to depend on the DM and the molecularweight of the pectin. The chemistry of low methoxyl pectin gelation isdescribed by Axelos and Thibault in “The Chemistry and Technology ofPectin”, Academic Press, New York, pp. 109-118, (1991).

Various prior art documents discuss the potential use of pectin as abioadhesive and gelling material. Studies by Smart et al, J. Pharm.Pharmacol. 36, 295 (1984) in relation to the adhesiveness of variousmaterials to mucus have shown that pectin is poorly adhesive in in vitrotests. A tablet capable of adhering to the mucus membrane containingpectin has been described in EP 306 454. Oechslein et al (Int. J.Pharm., 139, (1994), 25-32), have described the potential of variouspowder formulations to enhance the nasal absorption of the somatostatinanalogue peptide octreotide. Pectin (type FPA) powder was used, and gaverise to an increase in the absolute bioavailability of the drug ascompared to the drug administered in a saline solution. In none of thesedocuments was the use of a solution formulation containing a pectin witha low DE, or a pectin that gels in contact with nasal secretions,described.

Pectin has also been studied as a mucoadhesive ophthalmic material byChetoni et al (Bull. Chem. Farm., 135, 147 (1996)). Salt complexes ofdrugs with pectin for administration to the oral mucosa as patches havebeen described by Burgalassi et al, World Meet. Pharm. Biopharm. Pharm.Technol., (1995), p. 839, APGI, Paris. Popovici and Szasz (in “Buccaland Nasal Administration as Alternatives to Parenteral Administration”,Minutes of a European Symposium (1992), Duchene, D., Ed., Sante, Paris,France. p. 292-6) have described mucoadhesive hydrogels containingcellulose and pectin and a bivalent cation in the form of magnesium. Theuse of a low DE pectin as a solution that would gel in contact withmucosal surfaces was not described in any of these documents.

U.S. Pat. No. 4,826,683 describes a nasal decongestant containingvegetable oil, aloe vera, zinc, vitamin C, vitamin A, vitamin E, vitaminB6, biotin, and fruit pectin. The content of fruit pectin was to amaximum of 2 g per liter. The solubilized fruit pectin supplied byGeneral Foods under the trade name “Certo” was preferred. JP 62236862describes an artificial mucus composed of a mixture of a spinnable watersoluble polymer and a polysaccharide, protein or vinyl polymer. Pectinis listed as a suitable polysaccharide, though the type of pectin is notspecified.

U.S. Pat. No. 5,147,648 (EP 289 512) describes a pharmaceuticalformulation made from at least two components which, when addedseparately, can form a gel for treating a mucosa. The two components areapplied separately to the same area of a mucous membrane. The componentsmay be added simultaneously or sequentially. One of the gel formingsolution components includes a calcium salt (e.g., calcium gluconate)and the other may include a pectin. There is no suggestion in this priorart document that a solution comprising pectin may be administered as asingle component, in the absence of a separately applied solution ofcalcium ions, which will gel once in contact with the mucosa.

U.S. Pat. No. 5,318,780 describes aqueous pharmaceutical vehiclescontaining two components, a film forming polymer (e.g., pectin) and anionic polysaccharide, which are then gelled in situ by contacting themixture with a counter-ion. Polygalacturonic acids such as pectin arementioned in an extensive listing of representative useful polymers forapplication in the eye as corneal mastis protective corneal shields. Noexamples of the use of a pectin solution alone, nor of pectins with alow DE, or pectins that would gel in contact with the mucosa, aredisclosed.

The preparation of pectin beads by ionotropic gelation has beendescribed by Aydin and Akburfa (1996) Int. J. Pharm., 137, 133-136.

In summary, although it is known in the art that all pectins will formgels in the presence of calcium ions, for the pectins employedpreviously in pharmaceutical systems to be applied to mucosal surfaces,it has been hitherto understood that high levels of calcium are needed,which levels are well above physiological concentrations. This hasnecessitated the utilization of pectin systems which are applied eitherin the form of preformed gels, or before or after the addition ofexogenous calcium in order to produce a gel in situ. That liquids(especially solutions) comprising low DE pectins may be applied as such,and may gel upon, or just after, application to mucosa is neitherdescribed nor suggested in any of the aforementioned prior artdocuments. Further, the importance of the DE of pectin upon suchgelation properties is not mentioned in any of these prior artdocuments.

BRIEF SUMMARY OF THE INVENTION

The invention provides a single component liquid pharmaceuticalcomposition for administration to a mucosal surface that includes (i) atherapeutic agent, (ii) a pectin with a low degree of esterification,(iii) and a aqueous carrier. The aqueous carrier gels or can be adaptedto gel at the site of application.

The invention also provides a kit of parts that includes a liquidpharmaceutical composition for administration to a mucosal surface. Thecomposition of the kit of parts includes a therapeutic agent, a pectinwith a low degree of esterification, and an aqueous carrier. Thecomposition gels or is adapted to gel at the site of application.Additionally, the kit does not include a solution of divalent metal ionsto be added extraneously to the surface. The kit of parts of theinvention may be packaged and presented with instructions to administerthe composition to the mucosal surface in the absence of an extraneoussource of divalent metal ions.

The invention is also directed to a pharmaceutical gel compositionobtainable by applying a liquid composition, comprising a therapeuticagent, a pectin with a low degree of esterification, and an aqueouscarrier for application to a mucosal surface of a mammalian patient inthe absence of extraneous application of a solution of divalent metalions to the surface.

The invention also describes a method of treatment of a patient. Themethod comprises the administration of a liquid pharmaceuticalcomposition. The composition includes a therapeutic agent, a pectin witha low degree of esterification, and an aqueous carrier. The compositiongels or is adapted to gel at the site of application to a mucosalsurface of the patient in the absence of extraneous application of asolution of divalent metal ions to the surface.

Further described herein is a method of treatment of prophylaxis of adisease that comprises administration of a liquid pharmaceuticalcomposition. The composition includes a therapeutic agent that iseffective against the disease, a pectin with a low degree ofesterification, and an aqueous carrier. The composition gels or isadapted to gel at the site of the application. The composition isapplied to a mucosal surface of a patient in need of such treatment inthe absence of extraneous application of a solution of divalent metalions to the surface.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing summary, as well as the following detailed description ofpreferred embodiments of the invention, will be better understood whenread in conjunction with the appended drawings. For the purpose ofillustrating the invention, there is shown in the drawings embodimentswhich are presently preferred. It should be understood, however, thatthe invention is illustrated, but in no way limited, by the followingexamples with reference to the figures in which:

FIG. 1 shows the effect of systemic uptake of salmon calcitonin whenadministered intranasally to sheep in formulations comprising low DEpectin.

FIG. 2 shows the cumulative release/diffusion of fexofenadine HCl fromHP-β-CD and HP-β-CD/pectin 100 solutions to simulated nasal electrolytesolution.

DETAILED DESCRIPTION OF THE INVENTION

We have now found, surprisingly, that certain pectin materials, namelythose with a low DE, may be administered in the form of singlecomponent, simple liquid formulations (i.e., in an aqueous carrier)which will gel, or can be readily adapted to gel, upon application tomucosa in the nasal, rectal, and vaginal cavities, in the eye, or at theback of the throat. We have also found, surprisingly, that gelation mayoccur at physiologically acceptable pH values in the presence of verymuch reduced calcium concentrations, i,e., those which can be foundphysiologically in the nasal secretions, as well as in the vaginallumen, the rectal cavity, and the tear fluid of the eye.

According to a first aspect of the invention there is provided a singlecomponent liquid pharmaceutical composition for administration to amucosal surface comprising a therapeutic agent, a pectin with a low DEand an aqueous carrier, that gels or can be adapted to gel at the siteof application.

We have found, in particular, that such compositions gel, or can beadapted to gel, at the site of, and upon, or just after, application toa mucosal surface in the absence of an extraneously (i.e., separatelyand/or independently) applied (simultaneously or sequentially) solutionof calcium (or other divalent metal) ions. There is thus provided asingle component liquid pharmaceutical composition for applicationdirectly to a mucosal surface comprising a therapeutic agent, a pectinwith a low DE and an aqueous carrier, which composition is adapted togel at the site of application in the absence of an extraneous source(e.g., solution) of divalent metal ions applied to the same site.

According to a further aspect of the invention, there is provided a kitof parts comprising a liquid pharmaceutical composition foradministration to a mucosal surface, comprising a therapeutic agent, apectin with a low DE and an aqueous carrier, provided that the kit doesnot comprise a solution of divalent metal ions to be added extraneouslyto the surface.

In particular, there is provided a kit of parts comprising a liquidpharmaceutical composition for administration to a mucosal surface,which composition comprises a therapeutic agent, a pectin with a low DEand an aqueous carrier, and which kit of parts is packaged and presentedwith instructions to administer the composition to the surface in theabsence of an extraneous source of divalent metal ions.

The liquid pharmaceutical compositions for administration to mucosalsurfaces comprising therapeutic agent, low DE pectin and aqueouscarrier, which are, or are to be, administered as a single component,and which gel, or are adapted to gel, in the absence of an extraneoussource of divalent metal ions are referred to hereinafter as “thecompositions of the invention”.

By “liquid” composition, we mean a composition which is in the form of amobile fluid upon application to the mucosa. The compositions of theinvention are in the form of an aqueous formulation comprising asolution, a suspension, or an emulsion, including pectin and therapeuticagent, in water. The compositions of the invention will gel, or may beadapted to gel, upon, or shortly (e.g., up to 5 minutes) after,application, to a form a solid or semi-solid gel material, which gel issuitable to provide a retaining effect at the site of administration.

By “degree of esterification (DE)”, it is meant the percentage ofgalacturonic acid 25 units which are esterified, for example asdescribed in the article by Walter in “The Chemistry and Technology ofPectin”, Academic Press, New York (1991), p. 192. By “low DE”, it ismeant a pectin in which less than 50%, and more preferably less than35%, of the galacturonic acid units are esterified.

The term “extraneous source” of divalent metal ions includes a separateand/or independent (i.e. exogenous) source of such ions. Ions which arepresent in a gel resulting from administration of a composition of theinvention to a mucosa are not derived from either the composition, orfrom the bodily secretions of the patient to which the composition is tobe applied (e.g., endogenous ions derived from nasal secretions, tearfluid, etc.). Divalent metal ions which may be mentioned include calciumions.

According to a further aspect of the invention, there is provided apharmaceutical gel composition obtainable by applying a liquidcomposition, comprising a therapeutic agent, a pectin with a low DE andan aqueous carrier, to a mucosal surface of a mammalian patient in theabsence of extraneous application of a solution of divalent metal ionsto the surface.

The gels so formed upon contact with mucosal surfaces will contain onlyendogenous divalent metal ions (i.e., those derived directly from bodilysecretions) and will not include exogenous divalent metal ions (i.e.,those derived from an extraneous source). According to a further aspectof the invention there is provided a pharmaceutical gel composition,which gel comprises a therapeutic agent and a pectin with a low DE,which gel is obtainable by applying a liquid composition, comprising thetherapeutic agent and pectin in an aqueous carrier, to a mucosalsurface, and which gel is substantially free of divalent metal ionsderived from an extraneous source applied to the mucosal surface before,or at the same time as, or after, the liquid composition is applied.

Because the compositions of the invention are not added in conjunctionwith an extraneous source of such ions, by “substantially free” ofdivalent metal ions, it is meant greater than 97%, preferably greaterthan 99%, more preferably greater than 99.9%, and especially greaterthan 99.99% free.

Pectins with a low DE can be obtained from known sources, or can beobtained via de-esterification of high DE pectins (which may be obtainedfrom, for example, Sigrna Fine Chemicals), in accordance with knowntechniques, such as those described in the article by Rollin in“Industrial Gums”, Academic Press, New York (1993) p. 257, or asdescribed hereinbefore. Low DE pectin may, for example, be obtained fromCopenhagen Pectin A/S as the commercial material known as Slendid Type100 and Slendid Type 110. These pectins have been extracted from citruspeel and standardized by the addition of sucrose. The standardizationprocess is as described by Rollin in the above-mentioned article. The DEis less than 50% for both pectins and of the order of 10% for type 100and 35% for type 110. Further materials which may be employed includeGENU pectin types LM 1912 CS and Pomosin pectin types LM 12 CG and LM 18CG.

The compositions of the invention may be prepared by dissolving ordispersing the pectin of low DE and therapeutic agent in an aqueoussystem, to form a solution, a suspension or an emulsion in accordancewith known techniques. For example, the therapeutic agent may bedissolved in a prior prepared aqueous solution of the pectin, or may beadded as, or to form, a suspension in an aqueous system, where the drugparticles are less than 100 microns in size, preferably between 1 and 20microns. Alternatively, drug may be dissolved or suspended in a suitableoily vehicle such as a vegetable oil, and then dispersed into theaqueous pectin solution to form an emulsion. It will be appreciated bythose skilled in the art that the type of aqueous formulation sodeveloped will depend upon mucosa to be treated, as well as the dose,and the physical characteristics and properties, of the drug (e.g., itssolubility, basicity etc.).

The concentration of low DE pectin in compositions of the inventiondepends upon the nature of the pectin, the presence of other components,and other factors which influence gelation properties of the composition(see below), but may be from 1 g/L to 100 g/L, and is preferably from 1g/L to 50 g/L, more preferably from 2 g/L to 10 g/L and especially from5 g/L to 10 g/L.

Compositions of the invention may be used with a view to the preventionof a major problem in the delivery of drugs to the nose for localtreatment, namely the rapid mucociliary clearance mechanism. Thisnatural process, which removes deposited material from the front of thenose to the throat, can clear material from the nose with a half-time ofabout 10 to 20 minutes. Such clearance rates can be measured readily inman using the saccharin clearance test or by gamma scintigraphy (Aspdenet al, J. Pharm. Sci., 86, 509 (1997); Illum et al, Int. J. Pharm., 39(1987) 189-199).

Compositions of the invention may be employed to retain a therapeuticagent which is intended to act locally at a mucosal surface for arelatively long period when compared to mucosal delivery systems knownin the art. If the therapeutic agent is easily absorbed, absorption maybe retarded, thus keeping more of the drug at the site of application,where it is needed.

Therapeutic agents which may be employed in the compositions of theinvention include, for nasal administration, drugs that are employedlocally to treat conditions such as rhinitis, viral infections, as wellas those which act as decongestants. The compositions of the inventionmay also be used as a way of improving the delivery of vaccines to thenose associated lymphoid tissue and for the better presentation of DNAfor the transfection of nasal epithelial cells.

The following list of therapeutic agents are suitable for use in thecompositions of the invention, for local treatment of a mucosal surface,is provided by way of illustration and is not meant to be exclusive:antiviral agents such as ICAM-1, pirovadir, acyclovir,bromovinyldeoxyuridine, α, β and γ-interferon, zidovudine; decongestantssuch as oxymetazaline; anti-allergic agents, such as sodium cromoglycateand budesonide; steroids, such as fluticazone; vaccines, such as DNA,influenza, pertussis, measles and diphtheria vaccines; antibacterialagents; antifungal agents, such as amphotericin, nystatin; contraceptiveand/or spermicidal agents; antibodies especially for the treatment ofRSV infection in children; prophylactic agents against HIV;antihistamines, such as diphenhydramine hydrochloride; and genes.

Combinations of the above-mentioned therapeutic agents may also beemployed.

Compositions of the invention may also be employed to control the plasmalevel versus time profile for readily absorbable drugs which areintended to act systemically (i.e., to give a flatter profile), eitherby altering the rate of transport into the general circulation, or byretarding absorption of readily absorbable drugs. This can, for example,be of importance when side effects from high peak plasma levels are tobe avoided.

The compositions of the invention may thus be used for the modificationof the systemic absorption of mucosally administered drugs, including,but not limited to, apomorphine, nicotine, hyoscine hydrobromide,lignocaine, fentanyl, naratriptan, pheromones and propranolol.

Combinations of the above-mentioned therapeutic agents may also beemployed.

The term “therapeutic agents” is intended herein to include agents whichare suitable for use in the treatment, and in the prevention, ofdisease.

The compositions of the invention may be used to treat/preventdiseases/conditions in mammalian patients depending upon the therapeuticagent(s) which is/are employed. For the above, non-exhaustive lists oflocally acting and systemic drugs, diseases/conditions which may bementioned include those against which the therapeutic agent(s) inquestion are known to be effective, and include those specificallylisted for the drugs in question in Martindale, “The ExtraPharmacopoeia”, 31st Edition, Royal Pharmaceutical Society (1996).

Preferred drugs include nicotine and apomorphine.

The amount of therapeutic agent which may be employed in thecompositions of the invention will depend upon the agent which is used,and the disease to be treated, but may be in the range 0.01 to 40% w/w.However, it will be clear to the skilled person that suitable doses oftherapeutic agents can be readily determined non-inventively. Forexample, estimates of dosage can be made from known injectable productsassuming that from 0.1 to 90% of the dose is absorbed. Suitable singleunit doses are in the range 10 μg to 500 mg depending upon thetherapeutic agent(s) which is/are employed and the route ofadministration. Suitable daily doses are in the range 10 μg to 1 g/daydepending upon the therapeutic agent(s) which is/are employed and theroute of administration.

Most compositions comprising drug and a low DE pectin will gel uponapplication at the site of application, i.e., upon, or shortly (e.g., upto 5 minutes) after, contact with the relevant mucosal surface. However,in some formulations, the nature of the drug and/or the pectin whichis/are employed may require that the composition is adapted such that itgels upon, or shortly (e.g., up to 1 minute) after, contact. This may beachieved readily via techniques which are well known to those skilled inthe art:

For example, the concentration of pectin may be selected such that theaqueous formulation will gel once in contact with the mucosal surface.

Furthermore, the addition of monovalent ions to aid the gelling processmay be required (for example, simple monovalent electrolytes, e.g.,NaCl, may be added to adapt the liquid formulation to gel, as well as toprovide isotonicity).

The quantity and nature of the drug in the aqueous formulation may alsohave an influence on the gelation properties. For example, the additionof a high level of a certain drugs, including those which are weak bases(such as nicotine), which are known to form reversible complexes withanionic materials such as pectin, may require a change in the ratiobetween drug and pectin, so that preferably 30%, more preferably 50%,and most preferably 60%, of the negative charges on the pectin moleculeare uncomplexed.

Alternatively, sugars in the form of, for example, sucrose can be addedto the formulation to aid gelation. Non-ionic polysaccharides (such ashydroxypropyl methyl cellulose) may also be used.

The pH of the composition has also been found to affect gelationproperties. The pH of the compositions of the invention may be from 2 to9, more preferably from 3 to 8 and most preferably from 4 to 7, takinginto account the gelation properties of the composition and theproperties of the therapeutic agent. For example, in general, we havefound that the lower the DE of the pectin, the lower the pH at which thecomposition will gel. pH may be adjusted in accordance with techniqueswhich will be well known to those skilled in the art, such as theaddition of pharmaceutically acceptable buffering agents, especiallythose of low ionic strength. Axelos and Thibault in “The Chemistry andTechnology of Pectin”, Academic Press, New York, pp. 109-118, (1991)describe how the gelation properties of low DE pectin solutions aresomewhat sensitive to pH and ionic strength.

The above-mentioned techniques, which may be used to adapt thecompositions of the invention to gel, may be investigated and determinedin the normal course of routine experimentation by those skilled in theart. Combinations of these techniques may also be employed in order toaffect gelation properties.

The compositions may also contain other additives in the form ofpharmaceutical excipients, such as preservatives (e.g., lowconcentrations of materials such as sodium metabisulphate), stabilizers,flavoring agents, absorption enhancers such as bile salts,phospholipids, as well as agents which are known to interact with thedrug, for example to form inclusion or salt-bridge complexes, andpromote a controlled release in the nasal cavity from the formed gel,such as cyclodextrins and ion exchange resins.

Additional pharmaceutically acceptable excipients which may be added tothe compositions of the invention include agents such as glycerol.

According to a further aspect of the invention there is provided aprocess for the preparation of a composition of the invention whichcomprises mixing together the therapeutic agent and the pectin in theaqueous carrier.

The compositions of the invention may be administered in suitable dosageforms, in accordance with techniques, and via delivery devices, all ofwhich are known to those skilled in the art. For example, for nasaldelivery, the compositions of the invention are preferably administeredby way of a spray device, for example the Pfeiffer metered dose pump orthe Valois metered dose pump, or via a liquid free flow system (such asnasal drops). For vaginal and rectal administration (infusion) asyringe-type applicator may be used, or plastics ampoules fitted with asuitable nozzle, where the contents of the ampoule can be delivered tothe vaginal or rectal surface via the application of a slight pressure.Suitable systems for delivery of the compositions of the invention tothe back of the throat include spray devices which are well known tothose skilled in the art. Suitable systems for delivery of thecompositions of the invention to eye include liquid free flow systemwhich are well known to those skilled in the art (such as eye drops).

The compositions of the invention have the advantage that they may bereadily administered to mucosal surfaces in the form of singlecomponent, simple liquid formulations, in the absence of an additionalcomponent comprising an extraneous source of divalent metal ions, usingdevices which are well known to those skilled in the art. Thecompositions of the invention also have the advantage that they gelupon, or shortly after, contact with mucosa, at physiologicallyacceptable pHs, in the presence of endogenous calcium (only) foundphysiologically in the nasal secretions, as well as in the vaginallumen, the rectal cavity and the tear fluid of the eye.

Compositions of the invention also have the advantage that they may beused to retain a locally-acting drug at a mucosal surface, or to controldrug absorption into the systemic circulation.

Compositions of the invention may also have the advantage that they maybe well accepted by patients, and may comprise materials that areapproved by regulatory authorities.

According to a further aspect of the invention there is provided amethod of treatment of a patient which comprises the administration of aliquid pharmaceutical composition, comprising a therapeutic agent, apectin with a low DE and an aqueous carrier, which composition gels oris adapted to gel at the site of application, to a mucosal surface ofthe patient in the absence of extraneous application of a solution ofdivalent metal ions to the surface.

There is provided further a method of treatment or prophylaxis of adisease which comprises administration of a composition of the inventionincluding a therapeutic agent which is effective against the disease toa mucosal surface of a patient in need of such treatment in the absenceof extraneous application of a solution of divalent metal ions to thesurface.

EXAMPLE 1 To Demonstrate that Pectins with Low DEs Gel Under SimulatedConditions of the Nasal Cavity while Pectins with Higher DEs Do Not

Materials:

-   -   Pectin, esterified, potassium salt (DE: 31%; lot 22H0548; Sigma)    -   Pectin, esterified, potassium salt (DE: 67%; lot 74H1093; Sigma)    -   Pectin, esterified (DE: 93%; lot 125H0123; Sigma).    -   Pectin, Slendid type 100 (lot 620970; Hercules; Denmark).    -   Pectin, Slendid type 110 (lot 626790; Hercules, Denmark).    -   Pectin, GENU type LM 12 CG (lot G 63481; Pomosin GmbH;        Hercules;, Germany).    -   Pectin, GENU type LM 18 CG (lot G 63484; Pomosin GmbH; Hercules;        Germany).    -   Sodium chloride (BDH).    -   Potassium chloride (BDH).    -   Calcium chloride dehydrate (Sigma).

A simulated nasal electrolyte (SNES) solution was prepared, composed ofthe following ingredients: Sodium chloride 8.77 g/L Potassium chloride2.98 g/L Calcium chloride dehydrate 0.59 g/L

The SNES was prepared in double strength:

-   -   3.508 g of sodium chloride, 1.192 g of potassium chloride and        0.236 g of calcium chloride dehydrate were weighed into three        weighing boats respectively, and    -   dissolved and transferred into a 200 mL volumetric flask.    -   The solution was stirred on a magnetic stirrer until the drug        had dissolved.    -   Water was added to volume.

Preparation of 20 g/L Pectin Solutions

-   -   1 g of each type of pectin was weighed into a 100 mL bottle.    -   50 mL of ultrapure water was added to each bottle.    -   The content was stirred on a magnetic stirrer until pectin had        dissolved, and    -   the pH of the solution was measured and adjusted to pH 4 or pH        6.5 with 0.1 M sodium hydroxide solution.

Preparation of various formulations containing SNES and pectin withdifferent concentrations (2 to 10 g/L)

-   -   Appropriate volumes of 20 g/L pectin solution, to obtain the        final concentrations of 2, 3, 4, 5, 6, 7, 8, 9 and 10 g/L, were        measured in a series of 10 mL screw capped glass tubes.    -   Appropriate volumes of water were added to obtain a total volume        of 2.5 mL firstly, then 2.5 mL of the two fold concentration        SNES was added.    -   The tubes were cooled in an ice water bath for 15 minutes.    -   The test tubes were tilted to check the phase state and flow        property.    -   The tubes were vigorously shaken to check the phase state and        flow property again.

Results

The results are shown in Table 1:

-   -   1. Pectin type 100 and 110 gelled with simulated nasal        electrolyte solution when the final concentration of pectin        was >2 g/L and formed a strong gel when the final concentration        was >4 g/L at pH values of 4 and 6.5. The gel was transparent        and homogeneous. The strength of gel increased with the        increasing pectin concentration in system.    -   2. Pectin type LM 12 CG and LM 18 CG gelled at final pectin        concentrations of 4 g/L and 6 g/L (pH 4) and 4 g/L (pH 6.5)        respectively. These two pectin types only formed solid gels at        pH 6.5 and at concentrations higher than 6 g/L and 8 g/L        respectively.    -   3 . Pectin with a DE of 31% (Sigma) gelled at a concentration        of >2 g/L and formed a solid gel at concentrations >4 g/L.        Pectin 67% and 93% did not form solid gels at concentrations up        to 10 g/L at neither pH 4 nor at pH 6.5.

EXAMPLE 2 Nasal Drug Formulation Prepared from Pectins with Low DEs

Formulations were prepared containing drugs in the form of nicotine (aweak base) and cromolyn sodium (sodium cromoglycate; a weak acid).Pectin formulations were prepared at a pectin concentration of 10 mg/mLusing Slendid 100 and Slendid 110. The formulations were mixed with thesimulated nasal electrolyte solution (the method of preparation of whichwas as in Example 1). The formulations were filled into a nasal deliverydevice (Pfeiffer metered dose pump) and the spray properties evaluatedby visual examination.

The gelation of the formulation in the nasal electrolyte solution wasevaluated as solution, gel or solid by visual observation and the flowproperties before and after shaking. The results, which are set out inTable 2, show that when the formulation contained a weak acid (cromolynsodium), gelation occurred in the nasal electrolyte solution. When theformulation contained a high level of a weak base (nicotine) thengelation did not occur.

It is believed that the reason for this difference is that the ionizednicotine may interact with the charged carboxyl groups on the pectinmolecules and thereby influence the gelation characteristics of the lowesterified pectin. Thus, with weakly basic drugs, a person skilled inthe art is able to adjust the pectin concentration to take thisinteraction into account (see above).

EXAMPLE 3 To Demonstrate that Nasal Formulations Containing Low DEPectin do not Enhance the Systemic Uptake of a Poorly Absorbed Drug

For the local delivery of drugs it is important to retain the drug atits site of action, namely the nasal, rectal and vaginal cavities. Insuch cases, the formulation should not enhance the absorption of thedrug. It is known that some bioadhesive gelling formulations mayincrease systemic uptake. Therefore, experiments have been conducted inan animal model to demonstrate that pectins with low DE do not enhancethe nasal uptake (systemically) of a model polar drug, salmon calcitonin(S-CT).

Sheep

Eight female, cross-bred sheep of known weight were used in this study.The average weight of the sheep was in the region of 60 kg. The sheepwere weighed and labeled 1 to 8. An in-dwelling Secalon cannula fittedwith a flowswitch was placed approximately 15 cm into one of theexternal jugular veins of each animal on the first day of the study.Whenever necessary, the cannula was kept patent by flushing it withheparinised (25 IU/mL) 0.9% saline solution. This cannula remainedin-dwelling in the jugular vein of each animal for the duration of thestudy and was removed upon completion of the study.

Preparation of Salmon Calcitonin (S-CT) Formulations

Two S-CT formulations were prepared. Each formulation contained 2000IU/mL S-CT, which was sufficient material to administer a dose of 20IU/kg in a volume of 0.01 mL/kg. The sheep were randomly divided intotwo groups of four animals and each group was dosed with a differentS-CT formulation.

Summary of the Dose Groups S-CT Chitosan G210 Pectin Slendid 100Formulation (IU/kg) (mg/kg) (mg/kg) I 20 — — II 20 — 0.1

Prior to dose administration the sheep were sedated with an intravenousdose of Ketamine Vetalar® (100 mg/mL injection) at 2.25 mg/kg.Intranasal doses were administered at 0.01 mL/kg. The dose was dividedequally between each nostril. For dose administration, a bluelineumbilical cannula was inserted into the nostril of the sheep to a depthof 10 cm, before the delivery of the appropriate volume of solution froma 1 mL syringe.

Blood Sampling

Blood samples of 4 mL were collected from the cannulated jugular vein ofthe sheep at 15 and 5 minutes prior to S-CT administration and at 5, 15,30, 45, 60, 90, 120, 150, 180, 240, 300, 360, 420 and 480 minutespost-administration. They were then mixed gently in 4 mL heparinisedtubes and kept on crushed ice before plasma separation. Plasma wasseparated by centrifugation for 10 minutes at 4° C. approximately 3000rpm. Each plasma sample was divided into two equal aliquots ofapproximately 1 mL and stored at −20° C. One set of plasma samples wasused for calcium analysis.

Calcium Analysis

Plasma calcium analysis was performed by the Clinical ChemistryDepartment, Queens Medical Centre, University of Nottingham. The resultsshowed that for the formulation I and II the plasma calcium levels werevery similar and that the presence of pectin in the formulation did notlead to an increase in the systemic bioavailability of the model drug.

EXAMPLE 4 Simulated Nasal Electrolyte Solution-Pectin Gelling System forControlled Release of Fexofenadine Hydrochloride

Preparation of Formulations

Formulation 1—10 mg/mL fexofenadine HCl/100 mg/mL HP-β-CD: 2 g ofHP-β-CD was dissolved in 18-19 mL of water in a 20 mL volumetric flask.200 mg of fexofenadine was added to the solution and stirred until thedrug has dissolved. The pH of the solution was adjusted to 4.0, then thesolution was made up to volume with water.

Formulation 2—10 mg/mL fexofenadine HCl/100 mg/mL HP-β-CD/10 mg/mLpectin 100:

50 mg of pectin 100 (SLENDID type 100, Hercules, Denmark) was dissolvedin 5 mL of Formulation 1 in a 5 mL volumetric flask.

Release/Diffusion Testing

A Franz diffusion cell apparatus was set up in a closed loop arrangementand parameters were listed as follows:

-   -   Medium: Simulated nasal electrolyte solution    -   Temperature: 37° C.    -   Membrane: Cellulose nitrate, 0.45 Tm pore size    -   Volume of the closed loop arrangement: 8.8 mL    -   Stirring speed of a magnetic stirrer: 4    -   Peristaltic pump flow rate: 1 (The Cole-Parmer Masterflex        peristaltic pump, Model 7518-60, fitted with Masterflex L/Sth 14        silicone tubing)    -   Sample volume: 0.4 mL (contained 4 mg of fexofenadine HCl, the        maximum concentration of the drug in medium will be around 450        Tg/mL)    -   Wavelength: 260 nm

Results

The results are shown in FIG. 2. (Every point on the graphs represents amean value of two points.)

The maximum UV absorbance of Formulation 1 (control) reached during thediffusion experiment was used as 100% release to calculate thepercentage of release at each selected time point.

The results show a clear difference in release characteristics of thetwo formulations.

It will be appreciated by those skilled in the art that changes could bemade to the embodiments described above without departing from the broadinventive concept thereof. It is understood, therefore, that thisinvention is not limited to the particular embodiments disclosed, but itis intended to cover modifications within the spirit and scope of thepresent invention as defined by the appended claims.

1. A liquid pharmaceutical composition for administration to a mucosalsurface comprising: fentanyl, a pectin that has a degree ofesterification of less than 50%, and an aqueous carrier, wherein thecomposition gels or is adapted to gel at a site of application on themucosal surface in the absence of an extraneous source of divalent metalions.
 2. The composition of claim 1, wherein the pectin has a degree ofesterification that is less than 35%.
 3. The composition of claim 1,wherein the mucosal surface is the mucosa of the vagina, the mucosa ofthe rectum, the mucosa of the back of the throat, the mucosa of thenasal cavity, and the mucosa of the eye.
 4. The composition of claim 3,wherein the mucosal surface is the mucosa of the nasal cavity.
 5. Thecomposition of claim 1, wherein the composition is in a dosage formadapted for administration to the mucosal surface.
 6. The composition ofclaim 5, wherein the dosage form is selected from the group consistingof a free flowing system and a spray.
 7. The composition of claim 1,wherein the composition has a pH of 2 to
 9. 8. The composition of claim1, wherein the pectin is present in a concentration of 1 g/L to 100 g/L.9. The composition of claim 1, wherein the pectin is present in aconcentration of 1 g/L to 50 g/L.
 10. A method for treatment orprophylaxis of a disease, the method comprising administering acomposition according to claim 1 to a mucosal surface wherein thecomposition gels or is adapted to gel at a site of administration in theabsence of an extraneous source of divalent metal ions.
 11. Apharmaceutical gel composition prepared by applying a liquid compositionaccording to claim 1 to a mucosal surface of a mammal in the absence ofextraneous divalent metal ions.
 12. The pharmaceutical gel compositionof claim 11, wherein the pectin has a degree of esterification of lessthan 35%.
 13. A kit comprising a composition according to claim 1, butthe kit does not include a solution of divalent metal ions.
 14. The kitof claim 13, wherein the pectin has a degree of esterification that isless than 35%.
 15. The kit of claim 13, wherein the composition is in adosage form adapted for administration to the mucosal surface.
 16. Thekit of claim 15, wherein the dosage form is selected from the groupconsisting of a free flowing system and a spray.
 17. The kit of claim13, wherein the composition has a pH of 2 to
 9. 18. The kit of claim 13,wherein the pectin is present in the composition in a concentration of 1g/L to 100 g/L.
 19. The kit of claim 13, wherein the pectin is presentin the composition in a concentration of 1 g/L to 50 g/L.
 20. A methodof delivering fentanyl to a mucosal surface in a mammal comprisingadministering a liquid pharmaceutical composition according to claim 1to a mucosal surface of a mammal in the absence of extraneous divalentmetal ions.
 21. The method of claim 20, wherein the pectin has a degreeof esterification that is less than 35%.
 22. The method of claim 20,wherein the composition is in a dosage form adapted for administrationto the mucosal surface.
 23. The method of claim 22, wherein the dosageform is selected from the group consisting of a free flowing system anda spray.
 24. The method of claim 20, wherein the composition has a pH of2 to
 9. 25. The method of claim 20, wherein the pectin is present in thecomposition in a concentration of 1 g/L to 100 g/L.
 26. The method ofclaim 20, wherein the pectin is present in the composition in aconcentration of 1 g/L to 50 g/L.
 27. A method of preparing a liquidpharmaceutical composition comprising mixing fentanyl, a pectin that hasa degree of esterification of less than 50%, and a aqueous carrier toform a liquid composition that gels or is adapted to gel at a site ofadministration in the absence of divalent metal ions.
 28. The method ofclaim 27, wherein the pectin has a degree of esterification that is lessthan 35%.
 29. The method of claim 27, wherein the composition is in adosage form adapted for administration to the mucosal surface.
 30. Themethod of claim 29, wherein the dosage form is selected from the groupconsisting of a free flowing system and a spray.
 31. The method of claim27, wherein the composition has a pH of 2 to
 9. 32. The method of claim27, wherein the pectin is present in the composition in a concentrationof 1 g/L to 100 g/L.
 33. The method of claim 27, wherein the pectin ispresent in the composition in a concentration of 1 g/L to 50/L.